KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5

The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino ]-2,3-dihydro-1 H -imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on p hosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and pla telet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodieste rase 5 from canine trachea (K-i = 0.16 nM) more potently than sildenafil (K -i = 7.2 nM). The kinetic analysis revealed that KF31327 was a non-competit ive inhibitor. In the presence of nitroglycerin (nitric oxide generator), b oth compounds inhibited the collagen-induced aggregation of rabbit platelet s at less than 0.1 muM, augmenting intracellular cyclic GMP level without a ffecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 muM) of KF31327 was required to inhibit platelet aggrega tion and increased both cyclic nucleotide levels. However, 10 muM sildenafi l did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin, These results indicate that in the p resence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying th e inhibition without nitroglycerin might be related to a rise in intracellu lar cyclic AMP. (C) 2001 Elsevier Science B.V. All rights reserved.